Liver Transplantation

WALDO CONCEPCION, MD, FACS PROFESSOR OF SURGERY

CHIEF OF CLINICAL TRANSPLANTATION CHIEF OF PEDIATRIC KIDNEY TRANSPLANTATION

STANFORD UNIVERSITY HOSPITAL LUCILLE PACKARD CHILDREN’S HOSPITAL

15th Century wood panel

Limb transplantation by Saints Cosmos and

Damian

Transplanted leg of dead Moor onto a patient who

required transplantation

Leggenda Aura, Jacopo da Varagine 348

Alexis Carrel

(1873-1944)

“The problem of organ transplantation in man has

been solved.” -1905

Surgeon, Biologist

1904 Travelled University of Chicago and Rockefeller

Institute for Medical Research to develop the method

of end- to- end anastomosis of blood vessels

Nobel Prize in Physiology or Medicine (1912)

In recognition of vascular suture and pioneering work

in transplantation of blood vessels and organs

“From a clinical standpoint, the transplantation of organs may become

important…and may open new fields in therapy and biology.”

David Hume, M.D. “Father of Renal Transplantation”

• First successful human kidney transplant in 1947.

• Peter Brigham Hospital in Boston, MA

• Implanted in the forearm of a 29 y.o. female.

• Functioned for 4 days.

• No immunosuppression.

• Patient survived the procedure and recovered renal function.

Organ Transplantation

• Developed in the XX Century

• Fast development from experimental to

clinical

• Treatment of choice for End-Stage Organ

Failure

Historic Overview

• First Kidney transplant: 1954 by Dr. Joseph Murray

• First Liver transplant: 1963 by Dr. Thomas Starzl

• First Heart transplant : 1967 by Dr. Christian Barnard

• First Pancreas transplant: 1966 by Drs. Lillehei, Kelly

IMPORTANT ADVANCES IN TRANSPLANTATION-1990

• Organ Preservation

• Intra-operative monitoring and fluid management

• Immunosuppression

• Organ Donation

INTRA-OPERATIVE MONITORING AND FLUID MANAGEMENT

• Most common reason for intra-operative failure: hemorrhage

• Management of coagulopathy

• Management of hypothermia

• Aggressive Cardiac Monitoring

1950 1960 1970 1980 1990 2000 2010

First human

liver transplant

Collins solution

Viaspan solution

Azathioprine

Antilymphocyte

antisera

Steroids

OKT3

Cyclosporin

Tacrolimus

Mycophenolate

Mofetil

IL-2Ra

RAPA

First split liver transplant

First large animal

liver transplant First adult-to-

child transplant

First domino

liver transplant

First adult-to-adult

liver transplant

First liver

xenotransplant

First auxiliary

liver transplant

First reduced size liver transplant

First liver gene

therapy experiment

Veno-

venous

bypass

Patient Survival After Primary Liver Transplantation

5 4 3 2 1 0 0

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60

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100

AZA

CYA

CYA-UW

Tacrolimus

Time After Transplantation (years)

Pa

tie

nt

Su

rviv

al (%

)

Liver Transplantation in the U.S. Current Status

• 1-year patient survival: 85–90% in most centers

• 3-year survival 75-80%; 8-year survival 60-70%

• ~6,000 LT/year last 3 years in 110 centers

• >17,000 patients on LT waiting list

• ~1,800 deaths/year on waiting list last 3 years

• Mismatch between qualified candidates and available organs limits application of LT

www.unos.org

Donor Crisis (U.S.)

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Deaths

LTs

Listed Pts

www.unos.org

LT: Major Differences From Kidney Transplantation

• No artificial organ support

• Critical timing of transplantation

• High-risk living donor procedure

• Recurrent diseases

• Regenerative organ

• Donor matching (ABO) & immunosuppression

– “liver is immunologically privileged organ”

Selection for Liver Transplantation

Patient Selection Criteria for LT

• Accepted indications for LT

– Advanced chronic liver disease

– Acute liver failure

– Unresectable hepatic malignancy

– Inherited metabolic liver disease

• No alternative form of therapy

• No absolute contraindication to LT

• Willingness to comply with follow-up care

• Ability to provide for costs of LT

Keeffe EB. Selection of patients for liver transplantation.

In: Transplantation of the Liver, 3rd ed. 2001:5-34.

Liver Disease of Adult Recipients UNOS Database: 1990-92 vs. 1995-96

Primary

Diagnosis

Entire Sample

N = 17,044

1990-92

N = 5,857

1995-96

N = 6,059

Hepatitis C 26.2% 20.0% 30.8%

ALD 18.5% 21.3% 16.1%

AIH/Cryptogenic 16.7% 16.1% 17.2%

PBC 9.4% 10.3% 7.9%

PSC 8.7% 9.2% 8.3%

ALF 5.6% 5.7% 5.3%

Hepatitis B 4.6% 5.7% 4.3%

Metabolic disease 3.4% 3.6% 3.4%

Cancer 3.2% 4.9% 2.2%

Other 3.6% 3.5% 4.5%

Roberts MS, et al. Liver Transpl. 2004;10:886-897.

Reasons for Early Referral to Transplant Center

• Timely, stepwise evaluation of candidate

• Patient and family education about LT

• Intervention for confounding issues – Chemical dependence

– Obesity and other medical issues

• Financial counseling

• Program selection by patient – Center-specific results, facilities, relationships with

staff, etc.

Contraindications to LT: Absolute

• Active alcohol or substance abuse

• Advanced cardiopulmonary disease

• Systemic sepsis, unresponsive to Rx

• Multiorgan failure; multiple pressors

• Extrahepatic malignancy

• Severe pulmonary hypertension

• Severe psychiatric disease likely to affect compliance

Contraindications to LT: Relative

• General debility

• Advanced age

• Extensive prior abdominal surgery

• Extensive portal/mesenteric thrombosis

• Social isolation and limited support

• HIV seropositivity

• Cholangiocarcinoma

• Retransplantation for end-stage recurrent hepatitis C

Survival after Liver Transplantation

Survival after Adult LT UNOS Database 1997-2004

Survival (%)

Diagnosis 1 year 3 year 5 year

Noncholestatic cirrhosis 86 76 69

Cholestatic cirrhosis 90 85 80

Metabolic disease 90 85 81

Acute hepatic necrosis 82 73 70

Malignant neoplasm 86 70 58

Benign neoplasm 86 82 71

Other liver disease 80 72 64

http://www.optn/org/latestData/rptStrat.asp. Accessed January, 2007.

Determinants of Post-LT Outcome Shifting Paradigm

• Previous: surgery; early graft dysfunction; immediate post-op care; allograft rejection

• Current: management of recurrent disease; long-term management of consequences of immunosuppression, e.g., renal dysfunction, hypertension, diabetes, obesity, and dyslipidemia

Listing and Allocation

History of Allocation Policy • Before 1997, patients prioritized based on location

(home, hospital, ICU) and waiting time

• In 1997, categories of CLD defined by CTP score and location (status 2A, 2B, and 3), and patients ranked in priority based on time waiting

• As the waiting list grew, numbers of patients in each group increased, severity of disease became more heterogeneous, and waiting time rather than disease severity became the major determinant for allocation

I.O.M. Report. Organ Procurement and Transplantation: Assessing Current Policies and the

Potential Impact of the DHHS Final Rule. Washington, DC: National Academy Press; 1999. p.10.

Model for End-stage Liver Disease

Sample MELD Calculation

• Serum creatinine (1.9 mg/dL)

• Total bilirubin (4.2 mg/dL)

• INR (1.2)

MELD Score = (0.957 x loge1.9) + (0.378 x loge 4.2)

+ (1.120 x loge 1.2) + 0.643 = 2.039 x 10 = 20

www.mayo.edu search word MELD

CTP vs. MELD Score

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10

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6 8 10 12 14 16

CTP Score

ME

LD

Sco

re

r=0.55; p<0.001

Problems with MELD

• Unwieldy formula with log functions

• Sicker patients no longer kept in the hospital

• MELD score >25 not discriminatory

• Variability in assays for INR and creatinine

• What about other factors, e.g., older age, PSC, refractory ascites, refractory HE

• Does not address geographic variability or effect of blood type on access to donor organs

Modified TNM Staging*

Stage Definition I T1: one nodule 1.9 cm

II T2: one nodule 2-5 cm; 2 or 3 nodules, all < 3 cm

III T3: one nodule > 5 cm; 2 or 3 nodules, at least one > 3 cm

IVA1 T4a: four or more nodules, any size

IVA2 T4b: T2, T3, or T4a plus gross intrahepatic PV or HV involvement by imaging tests

IVB Any N1, any M1

*American Liver Tumor Study Group, 1998

HCC: Application of MELD

• UNOS implemented MELD score for allocation in 2/02

• T1 HCC assigned MELD score 24 (15% 3-mo mortality); T2 HCC assigned MELD score 29 (30% 3-mo mortality)

• Additional MELD points = 10% mortality added every 3 months until LT or progression beyond T2

• MELD score modified in 4/03 to score of 20 for T1 and score of 24 for T2

• MELD score modified in 11/03 to eliminate priority for T1

Assigned MELD Points for HCC

• Initial listing: 22 (15% probability of death)

• 3 months later: 25 (+10% probability of death)

• Each 3 months: 28 29 31 33

• Takes time to acquire higher MELD score

• Refer early

MELD/PELD: Special Cases Refer to Regional Review Board

• RRB review with assignment of MELD/PELD score that gives reasonable chance of organ offer within 3 months in that region

– HPS (hepatopulmonary syndrome)

– FAP (familial amyloidosis)

– Polycystic liver disease

– Others

MELD: Deceased Donor Liver Allocation

ADVANTAGED

• High MELD score

• Renal failure, anticoagulation

• Hepatocellular carcinoma

• Special diseases: amyloidosis, oxalosis

• Special conditions: HPS

DISADVANTAGED • Debilitating illness with

low MELD: pruritus, ascites, encephalopathy

• Cholestatic liver diseases

• Controversial indications: CCA, neuroendocrine tumors

Immunosuppressive Drugs:

Evolving Trends

Immunosuppressive Drugs

Post DJ, et al. Liver Transpl. 2005;11:1307-1314

1950 1960 1970 1980 1990 2000 2010

Azathioprine

Steroids

Cyclosporine

Tacrolimus

MMF

Sirolimus

FTY720

FK778

Anti-lymphocyte

antisera OKT3

Basiliximab

Daclizumab

Anti-thymocyte

globulin

1st OLT 1963

Immunosuppression 101

• Target the T cell to prevent ACR

• Balance between

– too little risk of rejection

– too much risk of toxicity

– monitor drug levels

• Many different combinations of drugs

• Risk of ACR is highest in 1st 4 months

– start with 2-3 drugs at higher levels

– with time fewer drugs at lower levels

• Levels managed by the LT center

Immunosuppression Trends

• Excessive immunosuppression associated with opportunistic infections, increased risk of malignancy, and aggressive recurrence of HCV

• Prior regimens: triple therapy; induction regimens; and frequent use of OKT3

• Current regimens: steroid withdrawal; calcineurin sparing; and avoidance of OKT3

• Goal: strike balance between prevention of rejection and avoidance of late adverse events, particularly nephrotoxicity; more use of MMF and sirolimus

Liver Transplantation for

Selected Diagnoses

Modified King’s College Criteria for LT for ALF

• Acetaminophen – Arterial pH <7.3, or – Concurrent findings of INR >6.5, serum creatinine

>3.4, stage 3 or 4 HE

• Other etiology – INR >6.5, or – Any 3 of following:

• INR >3.5 • Age <10 or >40 years • Serum bilirubin >17.5 mg/dL • HE >7 days after jaundice • Etiology: drug reaction or indeterminate

O’Grady JG et al. Gastroenterology 1989;97:439-445.

Hepatitis B

• LT considered a contraindications prior to current treatment options secondary to high rates of reinfection, graft loss and patient death

• Pretransplant control of replication (lamivudine, adefovir, tenofovir) now possible

• Postoperative HBIg plus nucleoside analogues are standard prophylaxis

• Recurrence of HBV currently rare, and most cases manageable

Yu AS, Keeffe EB. Clin Liver Dis 2003;7:551-72

Recurrent Hepatitis C

• Recurrent HCV universal and immediate after LT

• Recurrence of HCV associated with reduced QOL and worse graft and patient survival

• Risk factors for histologic recurrence: donor (age, steatosis, ischemic time, LDLT); recipient (age); and viral (HCV RNA level and quasispecies)

• 20% to 40% of recipients progress to cirrhosis within 5 years (vs. <5% of non-LT patients)

• Rate of progression from compensated to decompensation cirrhosis to death accelerated

Charlton M. Liver Transpl. 2005;11(Suppl 1):S57-S62.

Recurrent Hepatitis C

• HCV therapy in ESLD promising, but difficult

• Heavy immunosuppressive regimens associated with greater viral replication and graft damage

• Pre-emptive therapy only modestly effective

• Standard therapy (IFN + RBV) limited by immunocompromise, renal impairment and risk of rejection, but has SVR of ~20%

• PegIFN + RBV has SVR of 30% to 45%

• More potent drugs with fewer toxicities needed

Terrault NA. Clin Gastroenterol Hepatol. 2005;3(Suppl 2):S125-S131.

HEPATOCELLULAR CARCINOMA: EPIDEMIOLOGY

Most frequent primary liver tumor (80-90%). Western Africa constitute. Affects more than 600,000 people worldwide

annually. In United States, 16,000 patients are expected to die

from hepatocellular carcinoma in 2007. Case-fatality ratio is 0.8. Median survival rate of 6 months if untreated. 3 times more frequent in male than female. In patients with cirrhosis, the annual incidence of

hepatocellular carcinoma is 3-10%.

HEPATOCELLULAR CARCINOMA: RISK FACTORS

Persistent and long-lasting inflammation (hepatitis C, alcohol, alpha-1 antitrysin deficiency).

Direct genetic effect by DNA integration (hepatitis B , genetic hemochromatosis).

Hepatitis C is an RNA virus and does not integrate into host DNA.

Toxic factors (alcohol, aflatoxin, obesity, azo dyes, arimatic amines, chlorinated hydrocarbones, Thorotrast, smoking, porphyria, anabolic steroids, etc)

HEPATOCELLULAR CARCINOMA: PREVENTION

Hepatitis B vaccination.

Prevention of hepatitis C transmission by blood transfusion, piercing, needles).

Hepatitis C treatment (non-cirrhotic stages).

Prevent alcohol-induced liver injury by cessation programs.

Avoid grain storage in humid conditions (fava beans).

Public education on obesity.

Liver Transplantation for HCC

• Selection - Stage 2 limit

• Survival rates at four years: 85% overall (of whom 92% recurrence-free) (Mazzaferro 1996)

• Overall 5 year survival: 70-75% with recurrence rates <15% (Llovet 1999, Yao 2001)

• Liver transplantation offers the best outcome for those who make it to transplant

Recurrent Disease after

Liver Transplantation

Recurrence of Disease after LT

• Increasing problem as patients live longer after LT

• Some recurrent disease inconsequential, while other recurrence a cause of death or re-LT

• Potential requirement for re-LT an added burden to already limited resources for LT

• Results of re-LT inferior to initial LT (survival 62% vs. 87% at 1 year, and 54% vs. 77% at 3 year)1

1UNOS Update: UNOS Scientific Registry. 1996; p. 11-32.

Diseases That Do Not Recur after LT

• Extrahepatic biliary atresia • Fulminant hepatitis A • Fulminant hepatitis of unknown cause • Metabolic liver diseases (defect in

hepatocyte) – LT for hepatic complications, e.g.

• Wilson’s disease • Alpha-1-antitrypsin deficiency

– LT for extrahepatic complications, e.g. • Primary hyperoxaluria type I • Primary hypercholesterolemia

Diseases That May Recur after LT

• Hepatitis B

• Hepatitis C

• Primary biliary cirrhosis

• Primary sclerosing cholangitis

• Autoimmune hepatitis

• Malignant tumors

• Hemochromatosis

• Alcoholic liver disease

• Nonalcoholic steatohepatitis

• Budd-Chiari syndrome

Future of Liver Transplantation Expansion of Recent Developments

Deceased Donor Classifications

• Standard criteria donors (SCD) – Donor who is neither ECD or DCD

• Expanded criteria donors (ECD) – Donor characteristics with higher relative risk

of graft failure*

• Donation after cardiac death (DCD) – Donation from a patient whose heart has

irreversibly stopped beating

*Definition in evolution (?RR of graft failure >1.7 x expected); potential factors

include advanced donor age, steatosis, DCD, split liver, positive hepatitis

serologies, some donor causes of death, pressor use, significant down time

Expansion of Donor Pool

• Living donors: donor risk, higher rate of complications

• Older donor: higher PNF, higher recurrence rate of HCV

• Split liver: higher complication rate, labor intensive, disadvantage to primary recipient

• Marginal livers: increased risk of PNF • High-risk livers: some long-term risk • Domino transplant: amyloid donor

Living Donor Liver Transplantation

Liver Segments

2

3 4

1

5

7

6

8

Surgical Alternatives

• Cadaveric liver transplantation

° Reduced size (adult child)

° Split liver (left lobe child; right lobe adult)

• Living donor liver transplantation (LDLT)

° Left lateral segment (2 & 3): adult child, small adult

° Right lobe (5 through 8): adult adult

Split Liver Transplantation

Right lobe Left lobe

LDLT in the United States

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1991 1993 1995 1997 1999 2001 2003 2005

Adult

Peds

www.unos.org

Advantages of LDLT

• Decreased waiting time

• Extensive donor testing

• Reduced cold ischemic time

• Elective procedure

• Increased number of cadaver organs for others waiting for LT

Disadvantages of LDLT • Donor risk

– Mortality: 0.2% to 0.5%

– Morbidity: median 15% to 30%, primarily biliary complications and infections

– ? Economic, physical, psychological sequelae

• Recipient risk

– New procedure (track record?)

– Smaller liver mass

– Increased biliary complications

– Other (? higher HCV and HCC recurrence)

Middleton PF, et al. Liver Transpl. 2006;12:24-30.

Nadalin S, et al. HPB. 2006;8:10-21.

LDLT: Potential Concerns

• Transplantation performed earlier than

needed

• Non-standard uses of transplantation, e.g.,

advanced stage HCC

• Worse outcomes with HCV ?

Liver Transplantation: Summary Potential Future

• Development of effective artificial liver

support

• Immune tolerance protocols to allow

withdrawal of immunosuppression

• ? Xenotransplantation

• ? Hepatocyte transplantation

Hepatology • Rejection

• Recurrent Disease

Management of the LT patient

Gastroenterology • Biliary Strictures • Abdominal pain

• Diarrhea • Colon Cancer

Hepatology • Rejection

• Recurrent Disease

Gastroenterology • Biliary strictures • Abdominal pain

• Diarrhea • Colon cancer

Cardiology • CAD • HTN

Endocrinology • DM

• Hyperlipidemia • Obesity

• Osteoporosis

Nephrology • Renal failure

Oncology/ Hemat • PTLD • Cancer

Dermatology • Rash, Skin cancer

General Med. • Prevention

Infectious Dis. • CMV, EBV

Pulmonary • Pneumonia, TB

Rheumatology • Arthritis, Gout

Neurology • H/A, seizures

Management of the LT patient

Courtesy of Kelly Burik, U Calgary

LIVER TRANSPLANTATION

THE SURGERY...

THE SURGERY-WHAT THE SURGEON MAY NEED?

• ASSESSMENT OF CARDIO-PULMONARY STATUS

• LOW FILLING PRESSURES

• COAGULATION MANAGEMENT

• HEMODINAMIC STABILITY

• MANAGEMENT OF COMPLICATIONS( FIBRINOLYSIS, PULMONARY EMBOLISM, MALIGNANT HYPERTERMIA, AIR EMBOLISM, ETC)

• TEMPERATURE

• CLOSE COMMUNICATION WITH THE SURGEON AT ALL TIMES!!!

Liver Transplant

Liver Graft

Ready for Implantation

Successful Transplant

A New Beginning...

89.23

90.6

93.28

93.18

92.28

87.81 88.29 88.17

87.69 88.22

89.53

89.59

89.98 90.18

90.58

84

86

88

90

92

94

Jul-12 Jan-13 Jul-13 Jan-14 Jun-14

Patient Survival

SHC Observed SHC Expected National Average

86.02

87.1

89.76

91.15 91.03

85 85.16

84.89 84.76

85.74

86.49

86.57

87.29 87.62

87.96

82

84

86

88

90

92

Jul-12 Jan-13 Jul-13 Jan-14 Jun-14

Graft Survival

SHC Observed SHC Expected National Average

SRTR Liver Transplant 1 Year Post Transplant

Survival July 2012 to June 2014

• Extracorporeal support of liver function

• Continuous treatment of plasma ultrafiltrate for up to 5 days

• Ultrafiltration Circuit + ELAD Cartridges

4

ELAD Liver Support System

Current concepts

• Immune regulation

– Drug therapy

– Tolerance induction

– Immune monitoring

• Organ availability

– Preservation

– Regeneration and bioengineering

87

Bioprinted human bladder

Decellularization of vascularized organs and subsequent recellularization

Human iPS-derived tissue

Takahashi et al, Cell, 2007

Healthcare Education and Collaboration

Keys to success!

THANK YOU!